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Growth Hormone Exerts Hematopoietic Growth-Promoting Effects In Vivo and
Partially Counteracts the Myelosuppressive Effects of Azidothymidine
By William J. Murphy, Galia Tsarfaty, and Dan L. Longo
Recombinant human growth hormone (rhGH) was administered to mice to determine its effect on hematopoiesis.
BALB/c mice and mice with severe combined immune deficiency (SCID), which lack T cells and B cells, were administered intraperitoneal injections of rhGH for 7 days. Upon
analysis, both strains of mice exhibited an increase in splenic
and bone marrow hematopoietic progenitor cell content and
cellularity, indicating that rhGH can act as a hematopoietic
growth factor. C57BL/6 mice were then placed on azidothyAZT is a reverse transcriptaselinhibitor curmidine ,(AZT).
rently used as a treatment for acquired immune deficiency
syndrome (AIDS), but which also producessignificant myelotoxic effects. Treatment of mice with rhGH partially counteracted the myelosuppressiveproperties of AZT. Bone marrow
cellutarity, hematocrit values, white blood cell counts, and
splenic hematopoietic progenitor cell content were all significantly increased if rhGH (20 bg injected intraperitoneally
every other day) was concurrently administered with AZT.
Administration of ovine GH (ovGH), which, unlike rhGH, has
no effect on murine prolactin receptors, also prevented the
erythroid-suppressive effects of A73 in mice, but had no
significant effect on granulocyte counts. Thus, the effects of
GH are mediated at least in part through GH receptors in
vivo. Additionally, when mice were initially myelosuppressed by several weeks of AZT treatment, the subsequent
administration of ovGH resulted in an increase in splenic
hematopoietic progenitor cells. No significant pathologic
effects were observed in mice receiving either repeated rhGH
or ovGH injections. Thus, GH exerts significant direct hematopoietic growth-promoting effects in vivo and may be of
potential clinical use t o promote hematopoiesis in the face of
myelotoxic therapy.
This is a US government work. There are no restrictions on
its use.
G
MATERIALS AND METHODS
Assay for in vitro hematopoiesis. Spleen cells (SC) or bone
marrow cells (BMC) from mice were washed and resuspended in
Iscove’s modified Dulbecco’s medium with 10% fetal bovine
serum, 1% L-glutamine, and antibiotics (complete Iscove’s modified Dulbecco’s medium). Nucleated cells were counted on a
Coulter counter (Coulter). The cells were then plated in 0.3%
bactoagar (Difco Laboratories, Detroit, MI) in 35-mm Lux petri
dishes (Miles Laboratories, Inc, Naperville, IL) at a concentration
of 1 x 105 BMC or 5 x lo5spleen cells per plate. Colony formation
was stimulated in some instances with predetermined optimal
doses of growth-promoting cytokines such as recombinant murine
granulocyte-macrophage colony-stimulating factor (GM-CSF) at
10 ng/mL (Amgen Corporation, Thousand Oaks, CA) and purified
murine interleukin-3 (IL-3; 10 ng/mL) supplied by the Biological
Response Modifiers Program Repository (Frederick, MD). Plates
were incubated at 37°C for 7 days in 100% humidity, 5% CO2
atmosphere. All experiments had at least three mice per group and
were performed two to four times, with a representative experiment being shown. A Student’s t-test was performed to determine
if the values differed significantly (P < .001).
Treatment with GH. Mice in some groups received either 20 kg
rhGH (provided by Genentech, San Francisco, CA) or 20 kg of
ovine GH (ovGH, provided by the National Institute of Diabetes
and Digestive and Kidney Diseases, the Center for Population
Research of the National Institute of Child Health and Human
Development, and the Agricultural Research Service of the US
Department of Agriculture, as well as University of Maryland
School of Medicine, Baltimore, MD) resuspended in 0.2 mL
Mice. C57BLI6 (B6), BALBIc, and CB17 scidlscid (SCID)
mice were obtained from the Animal Production Facility (NCIFCRDC, Frederick, MD) and were not used until 8 weeks of age.
SCID mice were housed under specificpathogen-free conditions at
all times.
Hematopoietic analysis. Blood was collected from mice via the
lateral tail vein, using EDTA as an anticoagulant. Complete blood
counts were performed with a Coulter counter (Coulter, Hialeah,
FL) and differential cell counts were performed by microscopic
examination of Wright’s stained peripheral blood smears (MetPath, Inc, Rockville, MD). Samples were run through a Coulter
STKS (Coulter) and a manual differential count was performed.
Statisticswere performed comparingdifferent values using parametric analysis with the Student’s t-test. All experiments had at least
three mice per group and were performed at least three times.
From the Biological Response Modifiers Program, Division of
Cancer Treatment, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick MD.
Submitted February 11,1992; accepted May 19,1992.
Address reprint requests to William J. Murphy, PhD, Biological
Response Modifiers Program, NCI-Frederick Cancer Research and
Development Center, Bldg 567, Rm 141, Frederick MD 21 702-1201.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
This is a US government work. There are no restrictions on its use.
0006-4971/92/8006-OOO8$0.00/0
ROWTH HORMONE (GH) exerts a variety of growth
promoting effects on the body. G H has also been
implicated in immune development and function.’ There is
also evidence, primarily through in vitro analysis, that G H
can influence hematopoie~is.2,~
G H has been shown to
directly enhance erythropoiesis in vitro: and GH-deficient
dwarf mice have been reported to exhibit suppressed
splenic hematopoietic progenitor cell content.4 Additionally, G H has been shown to indirectly stimulate granulopoiesis in vitro through the release of secondary mediators such
as insulin-like growth factor-1 (IGF-l).3
Azidothymidine (AZT) is a reverse transcriptase inhibitor currently used as a treatment for acquired immune
deficiency syndrome (AIDS). One of the significant doselimiting toxicities of AZT involves an anemia and neutropenia arising from its myelotoxic effects on the m a r r o ~We
.~
examined whether recombinant human G H (rhGH) would
be an effective hematopoietic stimulating agent when administered in vivo and whether it would counteract the myelosuppressive properties of AZT. We report here that human
G H exerts significant hematopoietic growth-promoting effects in vivo, partially reverses the myelosuppression by
AZT, and may be of use clinically to promote hematopoiesis in the face of AZT or other myelotoxic therapy.
Blood, Vol80, No 6 (September 15). 1992: pp 1443-1447
1443
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1444
MURPHY, TSARFATY, AND LONG0
phosphate-buffered saline (PBS) and injected intraperitoneally
(IP) every other day until the mice were assayed. Mice not
receiving GH received daily IP injections of PBS.
Treatment with AZT. Mice received AZT (provided by Division
of AIDS, NIAID, Bethesda, MD) in their drinking water (1
mg/mL). Mice were then assayed weekly.
RESULTS
Administration of rhGH in vivo results in an increase in
hematopoieticprogenitor cells. To determine if rhGH could
exert hematopoietic growth promoting properties in vivo,
BALB/c mice and mice with severe combined immune
deficiency (SCID) were administered injections of 20 pg of
rhGH every other day for 7 days (a total of three injections).
A soft agar colony assay was then performed to determine
hematopoietic progenitor cell content of BMC and SC.
SCID mice were used because they lack T cells and B cells
due to an inability to productively rearrange their immune
receptor genes6 These mice allowed us to determine if the
hematopoietic effects of rhGH were due to the production
of cytokines by T cells because GH has been shown to
stimulate T cells.' The results showed that the administration of rhGH resulted in significant (P < .001) increases in
splenic and BMC colony-forming unit granulocyte-macrophage (CFU-GM) colonies in both BALB/c and SCID recipients (Table 1). Splenic cellularity was also increased after
rhGH treatment (Table 2). However, no significant effects
were detected on BMC cellularity or on peripheral blood
differential counts in the normal recipients, even when
100-pg doses of rhGH were administered (data not shown).
Additionally, no significant increases in body weight were
noted in the recipients receiving 20-pg injections of rhGH
(data not shown). Therefore, rhGH appears to exert
significant hematopoietic growth-promoting effects after in
vivo administration. Because rhGH treatment also increased the splenic hematopoietic progenitor cell content
in SCID mice, these results also suggest that rhGH is not
exerting its hematopoietic effects indirectly by inducing
colony-stimulating factor production by T cells.
rhGH treatment prevents the myelosuppressiveproperlies of
AZT. Because one of the dose-limiting toxicities of AZT
is anemia and neutropenia resulting from its myelotoxic
Table 1. Effect of rhGH Treatment on Hematopoietic Progenitor Cell
Content
Colonies
Strain (organ)
BALB/c (spleen)
BALB/c (spleen)
BALB/c (BMC)
BALB/c (BMC)
SClD (spleen)
SClD (spleen)
SClD (BMC)
SClD (BMC)
Treatment
rhGHt
rhGHt
-
rhGHt
rhGHt
Cytokines'
2.5
9.3
6.5
52.3
26.0
87.0
3:O
13.3
f
1.9
* 2.5$
1.8
* 12.4S
* 5.4
* 3.7$
2
2
0.0
1.7$
Media
020
020
020
02 0
020
020
O k O
OtO
*BMC or SC placed in soft agar with IL-3 and GM-CSF as described in
Materials and Methods.
tMice received 20 k g rhGH IP every other day for 7 days.
*Values significantly (P < ,001) greater than mice not receiving
rhGH.
Table 2. Effect of rhGH on Splenic and BMC Cellularity
Strain (organ)
Treatment
-
BALB/c (spleen)
BALB/c (spleen)
BALB/c (BMC)
BALB/c (BMC)
SClD (spleen)
SClD (spleen)
SClD (BMC)
SClD (BMC)
rhGH*
rhGH*
-
rhGH*
rhGH*
No. of Cells
(XlW
61.9 ? 5.2
93.1 ? 5.6t
31.8 f 3.3
33.0 f 2.7
17.5 ? 2.0
29.5 f 1.6t
21.1 2 1.8
27.8 2 0.7t
*Mice received 20 pg rhGH IP every other day for 7 days with
cellularity determined after 7 days. Values are representative of three
experiments containing three to four mice per group.
tValues significantly (P < .001) greater than mice not receiving
rhGH.
properties, we then examined whether concurrent treatment of mice with rhGH and AZT would result in an
improvement in their hematologic parameters. B6 mice
were placed on AZT (1 mg/mL in drinking water) for
several weeks. Upon analysis, these mice exhibited significantly lower (P < .001) BMC cellularity (Table 3), splenic
hematopoietic progenitor cell content (Table 4), hematocrit (HCT) (Fig l), and white blood cell (WBC) counts
(Fig 2) than control mice. These effects became more
pronounced the longer the mice were placed on AZT, with
most hematologic values approaching half the control
values. If mice were concurrently treated with 20-pg injections of rhGH administered every other day, all of these
hematologic parameters improved significantly (P c: .001).
The absolute number of segmented cells also increased in
response to rhGH treatment, increasing from 445 4 85/
mm3 to 840 ? 26/mm3 with mice placed on AZT and
examined at day 21 after concurrent rhGH treatment.
Similar results were obtained after 28 days (absolute
granulocyte count was 889 f l10/mm3 on AZT alone
compared with 1,485 2 33/mm3 in mice on AZT plus GH).
However, the hematologic parameters failed to attain
control values, even when higher doses (100 pg) of rhGH
Table 3. Effect of rhGH on Splenic or BMC Cellularity During AZT
Treatment
No. of Cells
Strain (organ)
~
66 (spleen)
66 (spleen)
66 (spleen)
66 (BMC)
66 (BMC)
66 (BMC)
~~
Treatment
(X106)
-
101.8 f 8.7
72.0 2 4.2t
100.3 t- 1.21
45.3 2 2.9
18.2 2 2.4t
32.2 2 3.72
~
~
AZT*
AZT, rhGHS
AZT*
AZT, rhGHS
Values are representative of three to four experiments with three
mice per group.
*Mice were placed on AZT (1 mg/mL) in drinking water for 21 days
before assay.
tValues significantly lower (P .: ,001) than control mice that did not
receive AZT.
*Mice were placed on AZT (1 mg/mL) in drinking water and rhGH (20
pg) IP injections every other day for 21 days before assay.
§Values significantly higher (P < .001) than mice receiving AZT but
no rhGH.
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1445
HEMATOPOIETIC EFFECTS OF GROWTH HORMONE
Table 4. Effect of rhGH on Hematopoietic Progenitor Cell Content in
Mice Placed on AZT
Colonies
Strain (organ)
Treatment
Cytokines*
Media
66 (spleen)
-
orto
66 (spleen)
66 (spleen)
66 (BMC)
66 (BMC)
66 (BMC)
AZTt
AZT, rhGH§
274.3 f 18.7
16.0 f 7.1*
43.5 rt 1.711
135.3 f 19.7
56.4 f 4.7*
120.0 f 20.311
-
AZT
AZT, rhGH
2
-
020
n
orto
1,
-I
:::
5.4
5.2
5.0
-I
4.8
4.6
orto
Of0
0 rt 0
Values are representative of three to four experiments with three
mice per group.
*BMC or SC placed with IL-3 and GM-CSF as described in Materials
and Methods.
tMice were placed on A7.T (1 m g l m l ) in drinking water for 21 days.
*Values significantly (P < .001) less than group not receiving AZT.
§Micealso received 20 pg rhGH IP every other day while on AZT.
IlValues significantly greater (P < ,001) than mice receiving AZT only.
were administered (data not shown). Additionally, the mice
exhibited no apparent pathologic effects from repeated
rhGH administration. The mice appeared to be in good
health throughout the study. They maintained a constant
weight and mice killed at the end of the study showed no
gross pathologic abnormality. Thus, treatment of mice with
rhGH partially ameliorates the anemia and neutropenia
arising from AZT treatment.
ovGH prevents and reverses the myelosuppression induced
by AZT treatment. Because hGH has been reported to be
capable of binding the prolactin receptor: it is possible that
rhGH can mediate its hematopoietic effects via the prolactin receptor pathway. To address this question, mice were
treated with 20-pg injections of ovGH every other day to
determine if ovGH would also counteract the myelosuppression caused by AZT treatment. ovGH does not bind to the
murine prolactin receptor and any hematopoietic effects it
exerts would be due to binding the GH receptor.’ The
44
6.0
1
T
3.8
3.8
Y
3.2
0
I
I
I
I
7
14
21
28
Dayn of Therapy
Fig 2. WBC counts (lO-*/mma)in mice receiving AZT (0)1mg/mL
in drinking HzO. In some groups, mice also received20-pg injectionsof
rhGH administered every other day (0).The points that appear to lack
error bars actually have standard errors that are smaller than the size
of the symbol and were thus omitted by the graphics program. (V)
Control.
results show that administration of ovGH can also counteract the myelosuppressiveeffects of AZT as determined by
HCT (Fig 3) and splenic hematopoietic progenitor cell
content (Table 5, experiment A). However, no significant
increases in WBC counts were obtained after ovGH treatment (data not shown).
Later ovGH treatment partially reverses the myelosuppression induced by AZT. It was then of interest to determine
if the administration of ovGH after myelosuppression was
already induced by AZT would improve hematologicparameters. Mice were administered AZT and after 3 weeks were
analyzed to confirm that they were myelosuppressed. They
then received 20-pg injections of ovGH administered every
other day for 7 and 14 days. Upon analysis of both time
points, significant improvement of splenic hematopoietic
progenitor cell content was noted in the ovGH-treated
44
43
42
41
34
36
32
1
1,
0
6
40
=
3s
T
I
I
I
I
I
7
14
21
28
35
Oaye of Therapy
Fig 1. HCT levels (vol %) in mice receiving AZT ( 0 )1 mg/mL in
drinking H20. In some groups, mice also received 20-pg injections of
rhGH administered every other day (0).The points that appear to lack
error ban actually have standard errors that are smaller than the size
of the symbol and were thus omitted by the graphics program. (V)
Control.
0
7
14
21
Daye of Therapy
Fig 3. HCT levels (vol %) In mice receiving AZT (0)1 mg/mL in
drinking HzO. In some groups, mice also received 20-pg injections of
ovGH administered every other day (0).
(V) Control.
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1446
MURPHY, TSARFATY, AND LONG0
Table 5. Effect of ovGH on Splenic Hematopoietic Progenitor Cell
Content in Mice Placed on AZT
Experiment*
Day of
Analysist
A
14
21
B
28
35
Colonies
Treatment
CytokinesS
Media
AZT
AZT+ovGH§
AZT
AZT+ ovGHB
AZT
AZT+ovGHT
AZT
AZT ovGHll
47212
7627
3020
622811
1327
362911
55215
116 2 1511
Of0
020
+
O r 0
Of0
020
020
Of0
0 f0
*Representative of two to three experiments with three mice per
group.
tNumber of days after mice were placed on AZT (1 mg/mL) in
drinking water.
SSC placed with IL-3 and GM-CSF as described in Materials and
Methods.
§Mice placed on AZT and received 20 pg of ovGH IP administered
every other day starting at day 0.
IlValues significantly(P < .001) greater than mice receivingAZT only.
(Mice were placed on AZT only for 21 days and were then treated
with 20 pg of ovGH every other day starting at day 21. Mice were
assayed later on day 28 (3 total injections of ovGH) and on day 35 (6
total injections of ovGH).
recipients (Table 5, experiment B), indicating that later
ovGH administration also results in the partial reversal of
myelosuppression induced by AZT. Similar results were
obtained with rhGH (data not shown).
DISCUSSION
GH has a variety of biologic effects in vivo and has been
suggested to exert effects on immune system development.'
We report here that rhGH also enhances hematopoiesis
when administered in vivo and can prevent or reverse the
myelosuppression induced by AZT. Both the anemia and
neutropenia resulting from AZT treatment were improved
by the administration of rhGH. It is important to note that
the hematopoietic growth-promoting effects of GH administration occurred at a dose regimen that did not result in
significant body weight gain. Thus, the doses required for
the manifestation of the hematopoietic effects of GH are
not so high that undesirable side effects (such as growth) or
significant pathology were noted.
The hematopoietic effects of rhGH could be due to both
direct and indirect mechanisms. The data using SCID mice
show that rhGH does not require T cells to produce its
hematopoietic effects. While GH has been shown to exert
hematopoietic growth-promoting effects in v i t r ~ ,little
~ , ~ is
known about its effects in vivo. It has been shown that GH
can directly enhance erythropoiesis in vitro2 and these
properties may explain the increase in HCT levels in mice
treated with both AZT and GH. Additionally, many of the
growth-promoting effects of GH are mediated by IGF-I,
which is produced in the liver in response to GH.8 GH has
also been shown to enhance granulopoiesis in vitro through
the induction of IGF-I release by adherent cells in the BM.3
Furthermore, BM stromal cells have been recently reported
to secrete IGF-1.9 Because the data presented here show
that rhGH administration to mice placed on AZT resulted
in the improvement of both WBC counts and HCTs, part of
the hematopoietic effects of GH administration may be due
to the induction of IGF-I release. However, the lack of
effect of ovGH on WBC counts suggests that rhGH may
mediate some of its granulopoietic effects via its ability to
stimulate prolactin receptor^.^ We have found that dwarf
mice, which lack GH and other neuroendocrine mediators,
such as IGF-I and prolactin$ also display suppressed
hematologic parameters, and treatment of the mice with
rhGH resulted in an improvement of hematologic parameters involving both myeloid and erythroid lineages.1° Preliminary results also indicate that treatment of mice with IGF-I
produces significant hematopoietic growth-promoting effects (manuscript in preparation).
Human GH has also been shown to be capable of binding
the prolactin r e ~ e p t o r and
, ~ some of the in vivo effects of
rhGH may be due to this binding capability. Indeed, we
have preliminary results indicating that prolactin exerts
significant hematopoietic growth-promotingproperties when
administered in vivo and can also counteract the myelosuppression caused by AZT treatment (manuscript in preparation). However, the data obtained using ovGH, which does
not bind the murine prolactin receptor: indicate that at
least some of the hematopoietic effects of rhGH are due to
GH receptor binding activity because ovGH administration
also yielded significant hematopoietic growth-promoting
effects, particularly in the erythroid series.
The minimal toxicities associated with rhGH administration make it an attractive therapeutic agent in patients with
AIDS undergoing AZT therapy." In contrast, many cytokines (GM-CSF and IL-1) currently used to augment
hematopoiesis clinically have significant dose-limiting toxicitiesI2 or affect only the neutropenia resulting from AZT
treatment.13The use of rhGH resulted in increases in both
erythroid- and myeloid-lineage cells and this may be more
efficacious, less toxic, and less expensive than administering
various myeloid-lineage-specific cytokines with or without
erythropoietin or transfusions. Whereas rhGH has been
shown to increase viral replication in human immunodeficiency virus (H1V)-infected T cells in vitro, coculture with
AZT abolished this activity, suggesting that rhGH does not
interfere with A Z T ' s reverse transcriptase-inhibiting funct i o n ~ . 'Because
~
GH has also been suggested to improve
T-cell function' and can result in increased body mass in
patients with AIDS,15the use of rhGH in AIDS may offer
other benefits in addition to the hematopoietic growthpromoting effects it may exert. HIV-infected individuals
have also been shown to have defects in neutrophil respiratory burst and defects in the microbicidal capability of their
neutrophils and monocytes.16 GH has been recently shown
to prime neutrophils for superoxide anion secretion" and
has also been shown to exert similar effects on macrophages.18 This suggests that rhGH may be of significant
therapeutic use in AIDS for a variety of hematologic and
immunologic reasons. However, while these results suggest
that GH administration can improve hematologic parame-
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
1447
HEMATOPOIETIC EFFECTS OF GROWTH HORMONE
ters after AZT treatment, it must be acknowledged that not
all the peripheral cytopenias seen in AIDS patients are
related to AZT toxicity alone. HIV infection may also
impair hematopoiesis. Because rhGH does not appear to
exert antiviral effects, it may have no effect on retroviralmediated suppression of hematopoiesis in HIV infection.
More work needs to be performed concerning the effects of
GH in situations where both AZT treatment and active
HIV infection occurs.
The use of rhGH may also improve hematopoietic
engraftment after BM transplantation (BMT) or improve
hematologic parameters in patients undergoing chemotherapy or radiation therapy. Preliminary results indicate both
GH and prolactin administrationresulted in greater hematopoietic engraftment in mice after syngeneic BMT (manuscript in preparation). Thus, rhGH exerts significant hematopoietic effects in vivo and may be of considerable clinical
use to augment hematopoiesis in humans.
ACKNOWLEDGMENT
The authors thank Terry Phillips for outstanding secretarial
services, Christie Harrison for superb technical assistance, Dr Ron
Hornung for critically reviewing the manuscript, and Dr Scott
Durum for helpful and stimulating discussions. The authors also
gratefully acknowledge the assistance of Drs Ron Hornung and
Ilan Tsarfatywith the statistical analysis and figures.
REFERENCES
1. Weigent DA, Blalock JE: Growth hormone and the immune
system. Prog Neuroendocrinimmunol3:231,1990
2. Golde DW, Bersch N, Li CH: Growth hormone: Speciesspecific stimulation of erythropoiesis in vitro. Science 1961112,
1976
3. Merchav S,Tatarsky I, Hochberg Z: Enhancement of human
granulopoiesis in vitro by biosynthetic insulin-like growth factor
Usomatomedin C and human growth hormone. J Clin Invest
81:791,1988
4. Duquesnoy RJ,Pedersen G M Immunologicand hematologic
deficiencies of the hypopituitary dwarf mouse, in Gershwin ME,
Merchant B (eds): Immunologic Defects in Laboratory Animals,
vol 1.New York, NY,Plenum, 1981,p 309
5. Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Hirsch
MS, Jackson GG, Durack DT, Nusinoff-Lehrman S, the AZT
Collaborative Working Group: The toxicity of azidothymidine
(AZT) in the treatment of patients with AIDS and AIDS-related
complex. A double-blind, placebo-controlled trial. N Engl J Med
317:192,1987
6. Schuler W, Weiler IJ, Schuler A, Phillips RA,Rosenberg N,
Mak TW, Kearney JF, Perry RP, Bosma MJ: Rearrangement of
antigen receptor genes is defective in mice with severe combined
immune deficiency. Cell 46963,1986
7. Cunningham BC, Ultsch M, DeVos AM, Mulkerrin MG,
Clauser KR, Wells JA. Dimerization of the extracellular domain of
the human growth hormone receptor by a single hormone molecule. Science 254:821,1991
8. D’Ercole AJ, Stiles AD, Underwood L E Tissue concentrations of somatomedin C Further evidence for multiple sites of
synthesis and paracrine or autocrine mechanisms of action. Proc
Natl Acad Sci USA 81:935,1984
9. Abboud SL, Bethel CR, Aron D C Secretion of insulinlike
growth factor I and insulinlike growth factor-binding proteins by
murine bone marrow stromal cells. J Clin Invest 88:470,1991
10. Murphy WJ, Durum SK, Anver MR, Longo D L Immuno-
logic and hematologic effects of neuroendocrine hormones: Studies on DW/J dwarf mice. J Immunol148:3799,1992
11. Salomon F, Cuneo RC, Hesp R, Sonksen PH: The effects of
treatment with recombinant human growth hormone on body
composition and metabolism in adults with growth hormone
deficiency. N Engl J Med 321:1797,1989
12. Smith JW 11, Urba WJ, Curti BD, Elwood L, Steis RG, Janik
JE, Sharfman WH, Miller L, Fenton RG, Conlon KC, Sznol M,
Creekmore SP, Wells N, Ruscetti FW,Keller JW, Hestdal K,
Shimizu M, Rossio J, Alvord WG, Oppenheim JJ, Longo D L The
toxic and hematologic effects of interleukin-1 alpha administered
in a phase I trial to patients with advanced malignancies. J Clin
Oncol (in press)
13. Levine JD, Allan JD, Tessitore JH, Falcone N, Galasso F,
Israel RJ, Groopman JE: Recombinant human granulocytemacrophage colony-stimulating factor ameliorates zidovudineinduced neutropenia in patients with acquired immunodeficiency
syndrome (AIDS)/AIDS-related complex. Blood 78:3148,1991
14. Laurence J, Grimison B, Gonenne A Effect of recombinant
human growth hormone on acute and chronic human immunodeficiency virus infection in vitro. Blood 79:467,1992
15. Krentz AJ, Koster FT,Crist D, Finn K, Boyle PJ, Schade
DS: Beneficial anthropometric effects of human growth hormone
in the treatment of AIDS. Clin Res 39:220A,1991 (abstr)
16. Smith PD, Ohura K, Masur H, Lane HC, Fauci AS, Wahl
SM: Monocyte function in the acquired immune deficiency syndrome: Defective chemotaxis. J Clin Invest 742121,1984
17. Fu Y-K, Arkins S, Shang Wang B, Kelley KW A novel role
of growth hormone and insulin-like growth factor-I. Priming
neutrophils for superoxide anion secretion. J Immunol 146:1602,
1991
18. Edwards CK 111, Ghiasuddin SM, Schepper JM, Yunger
LM, Kelley KW A newly defined property of somatotropin:
Priming of macrophages for production of superoxide anion.
Science 239:769,1988
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1992 80: 1443-1447
Growth hormone exerts hematopoietic growth-promoting effects in
vivo and partially counteracts the myelosuppressive effects of
azidothymidine
WJ Murphy, G Tsarfaty and DL Longo
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